Sarcoidosis is a systemic inflammatory disease of unknown cause, primarily affecting intrathoracic lymph nodes, lungs, and skin.
1 Small fiber neuropathy (SFN) is the result of damaged small myelinated (Aδ-fibers) and unmyelinated (C-fibers) nerve fibers. It is estimated that between 40% and 86% of patients with sarcoidosis suffer from SFN related symptoms.
2,3 There is no gold standard available for the diagnosis of SFN, but the Neurodiab criteria
4 are currently the best described criteria. These criteria are based on a large group of patients with diabetes and define three levels of diagnostic certainty.
For a diagnosis of possible SFN, symptoms and/or signs of neuropathic sensory symptoms should be present. A diagnosis of probable SFN additionally includes normal nerve conduction studies. To diagnose definite SFN, reduced intraepidermal nerve fiber density and/or abnormal quantitative sensory testing (QST) is also required.
4 A more recent reappraisal and validation study increased the reliability of the diagnosis by stating that at least two clinical signs should be present.
5
A very complex and time-consuming protocol has been proposed to determine the intraepidermal nerve fiber density.
6,7 QST shows varying reliability owing to the lack of standardized data.
8 Therefore, corneal confocal microscopy (CCM) has been investigated to detect SFN as a novel and minimally invasive alternative.
9,10 CCM generates in vivo images of the corneal sub-basal nerve plexus with resolutions comparable with ex vivo histochemical methods.
11
Although research has been conducted over the past 20 years to support its clinical use, CCM is still used primarily for research purposes only. Many hurdles have already been overcome in translating this technique from research to clinical use. For example, normative values are available
12 and a detailed protocol can be used for the accurate quantification of peripheral neuropathy.
13 In addition, a solid body of literature is currently available to support the usefulness of CCM in neurodegenerative diseases.
14
The cornea harbors a high nerve fiber density, up to 400 times higher compared with intraepidermal nerve fiber density.
15 Morphological changes of the sub-basal nerve plexus, such as the beading, length, branching, and tortuosity of the nerve fiber, are related to the presence of SFN.
11,16 There are several quantification methods available to analyze corneal nerve fibers
17 ranging from manual analysis,
18 semiautomatic analysis,
19 to automatic analysis.
20,21 Parameters such as corneal nerve fiber density (CNFD), corneal nerve fiber length (CNFL), corneal nerve branch density (CNBD), and nerve fiber area (NFA) can be identified using these techniques. However, guidelines on which analysis system should be used are lacking, as well as data on comparison of these different programs.
CNFD counts the number of main nerves in the image (no./mm
2), CNBD counts the number of branches (no./mm
2), and CNFL counts the total length of both main nerves and branches (mm/mm
2). Compared with CNFL, NFA is defined by the sum of total length of both main nerves and branches and the variation in the width (µm
2/mm
2) of nerve the fibers. As a result, NFA shows a nonlinear relation with CNFL and provides additional information when the structure but not the length of the small fibers changes. In the early stage of SFN, nerves tend to swell, whereas nerve degeneration can be observed in a more advanced stage of SFN. We illustrated this process in
Figure 1, which was based on the study describing this nerve pathology.
6 Based on the fact that, in the early phase of SFN development, NFL remains stable (
Fig. 1), it is suggested that the use of NFA increases the sensitivity for diagnosing SFN.
21 To date, no study has examined the correlation between NFA FIJI and ACCMetrics NFA. In patients with and without diabetes, there is good agreement between manual, semiautomatic, and automatic analyses of CNFL.
22
Looking at the different etiopathogeneses of diabetes and sarcoidosis, it remains to be seen whether the results found in patients with diabetes can be extrapolated to patients with sarcoidosis.
23 For example, it is known that patients with diabetes exhibit a more length-dependent variant of SFN, whereas SFN in patients with immune-mediated disease tends to present in a more patchy, non–length-dependent pattern.
24
The prevalence of ocular involvement in sarcoidosis ranges between 10-50%, with a higher prevalence reported in African Americans and women.
25 Ocular sarcoidosis could cause keratoconjunctivitis sicca, which then results in superficial punctate keratitis or band keratopathy, which in turn can affect the Bowman's epithelial layer.
26 In addition, uveitis can result in glaucoma, which can also contribute to decreased CNFD.
27
The aim of the current study was threefold. First, we investigated whether CCM results differ between patients with sarcoidosis with and without SFN. Secondly, we determined the correlation of CNFL calculated with manual analysis (CCMetrics
18), semiautomatic analysis (NeuronJ
19), and fully automatic analysis (ACCMetrics
20), and the correlation of NFA calculated with NFA FIJI
21 and ACCMetrics in patients with sarcoidosis. Finally, the potential value of automatic NFA analysis in diagnosing SFN was evaluated.